Selvapandiyan Angamuthu, Dey Ranadhir, Gannavaram Sreenivas, Solanki Sumit, Salotra Poonam, Nakhasi Hira L
Institute of Molecular Medicine, New Delhi, India.
Division of Emerging and Transfusion Transmitted Diseases, CBER, FDA, Bethesda, MD, USA.
Vaccine. 2014 Jun 30;32(31):3895-901. doi: 10.1016/j.vaccine.2014.05.009. Epub 2014 May 14.
Visceral leishmaniasis (VL) is fatal if not treated and is prevalent widely in the tropical and sub-tropical regions of world. VL is caused by the protozoan parasite Leishmania donovani or Leishmania infantum. Although several second generation vaccines have been licensed to protect dogs against VL, there are no effective vaccines against human VL [1]. Since people cured of leishmaniasis develop lifelong protection, development of live attenuated Leishmania parasites as vaccines, which can have controlled infection, may be a close surrogate to leishmanization. This can be achieved by deletion of genes involved in the regulation of growth and/or virulence of the parasite. Such mutant parasites generally do not revert to virulence in animal models even under conditions of induced immune suppression due to complete deletion of the essential gene(s). In the Leishmania life cycle, the intracellular amastigote form is the virulent form and causes disease in the mammalian hosts. We developed centrin gene deleted L. donovani parasites that displayed attenuated growth only in the amastigote stage and were found safe and efficacious against virulent challenge in the experimental animal models. Thus, targeting genes differentially expressed in the amastigote stage would potentially attenuate only the amastigote stage and hence controlled infectivity may be effective in developing immunity. This review lays out the strategies for attenuation of the growth of the amastigote form of Leishmania for use as live vaccine against leishmaniasis, with a focus on visceral leishmaniasis.
内脏利什曼病（VL）若不治疗会致命，在世界热带和亚热带地区广泛流行。VL由原生动物寄生虫杜氏利什曼原虫或婴儿利什曼原虫引起。尽管已有几种第二代疫苗被批准用于保护犬类免受VL感染，但尚无针对人类VL的有效疫苗[1]。由于治愈利什曼病的人会产生终身免疫力，开发减毒活利什曼原虫作为疫苗，使其能引发可控感染，可能是一种与接种利什曼原虫疗法相近的替代方法。这可以通过删除参与寄生虫生长和/或毒力调控的基因来实现。这类突变寄生虫在动物模型中通常不会恢复毒力，即使在诱导免疫抑制的条件下，因为关键基因已被完全删除。在利什曼原虫的生命周期中，细胞内无鞭毛体形式是致病形式，可在哺乳动物宿主中引发疾病。我们开发了缺失中心蛋白基因的杜氏利什曼原虫寄生虫，其仅在无鞭毛体阶段生长减弱，并且在实验动物模型中被证明对强毒株攻击安全且有效。因此，靶向在无鞭毛体阶段差异表达的基因可能仅使无鞭毛体阶段减毒，从而可控感染性可能对诱导免疫有效。本综述阐述了减弱利什曼原虫无鞭毛体形式生长以用作抗利什曼病活疫苗的策略，重点是内脏利什曼病。
